Nicotinic acid has been used for decades to reduce plasma cholesterol and triglycerides and raise HDL cholesterol levels, and has also been demonstrated to reduce risk of atherosclerotic cardiovascular disease. Recently, a receptor for nicotinic acid was discovered. Called HM74A (GPR109A), it is a G-protein coupled receptor that is part of a gene cluster of three highly homologous genes; the other two are known as HM74 (GPR109B) and GPR81. While expression of HM74A is substantial in adipose tissue, we and others have found that HM74A is also expressed in activated macrophages and vascular cells. Thus the possibility that nicotinic acid may have direct pharmacologic effects, and endogenous ligands direct physiologic effects, on the vasculature is intriguing. In this Project we will address the role of HM74A activation by nicotinic acid in: 1) modulating adipocyte metabolic function, cholesterol efflux, and adipokine secretion; 2) modulating macrophage lipid metabolism, cholesterol efflux, and inflammatory response; 3) modulating the vascular response to vascular injury and atherosclerosis; 4) the genetics and pharmacogenetics of this receptor family. The present studies are designed to address these questions using cell biological, animal model, and human investigative studies. These studies relate directly to studies in Project by FitzGerald by studying the interaction of HM74A with prostaglandin metabolism, specifically PGD2. They relate to Project by Reilly by focusing on the impact of HM74A in adipose tissue on vascular injury and by making use of two of the clinical studies organized and run through Project by Reilly. They make use of the Biomarker Core through the use of proteomic and lipidomic approaches to uncover novel pathways modulated by HM74A activation in different cell types. They utilize the Animal Model Core through a variety of vascular injury experiments in mice. These studies will advance our knowledge of the role of the nicotinic acid receptor HM74A in metabolism, inflammation, and vascular injury. The studies proposed here will fill in many of the knowledge gaps about nicotinic acid and its receptor with regard to cardiovascular disease, vascular injury, and the cutaneous flushing. As such, they will help to advance the science toward discovering better ways to target HM74A with the goal of reducing cardiovascular disease.